Renal cell carcinoma (RCC) is diagnosed in 64,000 people in the United States each year and causes over 13,000 deaths, and incidence has been steadily increasing over the past decades. Obesity is an established risk factor for RCC, but recent work has suggested the existence of an obesity paradox in which obese patients actually have improved survival after diagnosis compared to leaner patients. Such obesity paradoxes have also been put forward with respect to overall mortality, type 2 diabetes, heart disease, and kidney disease. This raises important questions for clinical practice regarding what advice to give patients diagnosed with disease, particularly in the presence of co-morbidities and the wide array of adverse health effects clearly associated with obesity. A critical question i whether this is a true finding or simply a result of confounding and other sources of bias. In this proposal, we seek to comprehensively study the association between obesity and RCC incidence and mortality using existing data from three large, long-term cohort studies: the Nurses' Health Study (NHS), the Health Professional's Follow-up Study (HPFS), and the Nurses' Health Study II (NHS II). Together, these prospective cohorts represent a unique resource with 738 confirmed cases of RCC, 169 RCC deaths, over 25 years of follow-up among 289,660 participants, and multiple assessments of obesity and other lifestyle and health factors both before and after diagnosis. We will assess the association between adult obesity and risk of total RCC and risk of fatal RCC. We will also study childhood body size and early adult body mass index with respect to RCC risk, and we will examine weight change during adulthood, weight change from early adulthood to midlife, and body size trajectory from childhood through adulthood. In addition, we will conduct survival analysis among RCC patients to assess the role of obesity and weight change before, at, and after diagnosis as they relate to cancer survival. In addition, we will use already collected information on health conditions and medication use to explore several possible pathways underlying the observed associations between obesity and RCC. We will quantify the extent to which hypertension and diabetes - established risk factors for RCC - drive the observed associations of obesity with incidence of total and fatal RCC, and we will investigate the role of blood pressure-lowering drugs and statins in RCC, and whether these drugs modify the obesity-RCC relationship. These investigations may provide clues about relevant biological pathways including insulin and glucose signaling, hypertension, and cholesterol metabolism, which can be followed up in future investigations using stored blood and tumor specimens in the cohorts. This project represents an unparalleled opportunity to efficiently explore in a single, large study population the role of obesity over time in both RCC incidence and survival. This will provide useful information to physicians and patients dealing with this increasingly common cancer, and it will provide clues as to the underlying tumor biology to drive future prevention and treatment efforts.